tbuckley/cabot-search huggingface dataset:
Investigation of predictive biomarkers in patients treated with atezolizumab monotherapy following definitive chemoradiotherapy for unresectable locally advanced esophageal squamous cell carcinoma (EPOC1802).
Authors: Hideaki Bando, Shogo Kumagai, Daisuke Kotani, Saori Mishima, Takumi Habu, Takahiro Tsushima, Hiroki Hara, Shigenori Kadowaki, Ken Kato, Keisho Chin, Kensei Yamaguchi, Shun-ichiro Kageyama, Hidehiro Hojo, Masaki Nakamura, Tachibana Hidenobu, Masashi Wakabayashi, Makoto Fukui, Nozomu Fuse, Hiroyoshi Nishikawa, Takashi Kojima
Journal: Journal of Clinical Oncology (2023)

416 Background: Platinum-based definitive chemoradiotherapy (dCRT) is the standard treatment for patients (pts) with unresectable locally advanced esophageal squamous cell carcinoma (ESCC), invading the aorta, vertebral body, or trachea. However, complete response (CR) rates are low (11–25%), with a median overall survival (OS) of 9–10 months. We previously reported atezolizumab following dCRT indicated promising 42.1% of confirmed CR (cCR) rate and 65.8% of 12-months OS (Bando H, et al., ESMO Congress 2022 ). Methods: We investigated predictive biomarkers for cCR in this multicenter phase II study. PD-L1 tumor proportion score (TPS) was examined with VENTANA PD-L1. Immunological phenotypes of tumor microenvironments were assessed with multiplex immunohistochemistry (mIHC) and multi-color flow cytometry (FCM). Cancer gene aberrations and gene expression were investigated with whole exome and whole transcriptome sequencing (WES/WTS), respectively. Results: In 35 pts with an evaluable PD-L1 TPS, the cCR rates of &lt;1% and ≥1% were 44.4% and 41.2%, respectively. In mIHC analysis of 28 pts, the number of CD3 + CD8 + PD-1 + T cells and CD3 + CD8 - FOXP3 + T cells prior to CRT in tumor tissue were significantly correlated with cCR and non-cCR, respectively (both are P&lt;0.05). In FCM analysis of 19 pts, tumor-infiltrating PD-1 + CD8 + T cells prior to CRT, after CRT, and after atezolizumab were significantly correlated with cCR (P&lt;0.05). On the other hand, CTLA-4 + FOXP3 high CD45RA - CD4 + regulatory T cells (Treg cells) after CRT were significantly correlated with non-cCR (P&lt;0.05). In WES of 27 pts, MYC amplification, EGFR mutation, PIK3CA mutation, PTEN mutation, and KEAP1 mutation were detected in pts with non-cCR. In WTS of 27 pts, gene expression signatures of IFN-γ response and inflammatory response were enhanced after CRT. Gene expression signatures of epithelial mesenchymal transition (EMT) and TGF-β signalings prior to CRT were significantly enriched in pts with cCR. Conclusions: Our biomarker analysis suggests that tumor-infiltrating PD-1 + CD8 + T cells prior to CRT may be a predictive biomarker for cCR of CRT followed by atezolizumab, and that several driver gene abnormalities, cancer intrinsic signatures and tumor-infiltrating Treg cells are associated with treatment resistance. These findings could enable subsequent biomarker-selected clinical trials and lead to the development of novel cancer immunotherapeutic strategies. Clinical trial information: UMIN000034373 .
Socioeconomic disparities causing delays in pancreatic cancer germline genetic testing.
Authors: Xianghui Zou, Daniel King, Baho Sidiqi, Sunita Patruni, Christopher Hollweg, Noah D. Kauff
Journal: Journal of Clinical Oncology (2023)

665 Background: Germline genetic testing is recommended for patients with pancreatic ductal adenocarcinoma (PDAC) and pre-diagnostic testing is offered to patients with a significant family history. However, only 36% of patients in our institution obtained genetic testing. We identified associations between patient social profiles (income, race, ethnicity, social work needs) and delays in obtaining germline genetic testing from New York’s largest healthcare system. Methods: Patients with PDAC were identified using billing records across our institution with an IRB-approved protocol. Median income was extrapolated using patient zip code. Date of diagnosis (DOD) was recorded as the date of biopsy or, if no biopsy was performed, the date of earliest lesion found on CT scan. Delays of testing was calculated as the difference between DOD and the date of germline sample collection. Results: Between Mar 2016 and Feb 2022, 305 patients with PDAC were identified, with 103 (36.3%) having reports found (F), and 202 (63.7%) not having reports found (NF). Availability of germline testing did not vary by median income (F: $95954, NF: $94368, t=0.414, p=0.68). There was no significant difference in the geographic distribution either (gender p=0.92, race p=0.92, ethnicity p=0.16). Pearson analysis between income (x) and delays of testing (y) showed a negative correlation (y=-0.0028x+316, r 2 =0.058, p=0.014). African American and Hispanic patients, grouped for this analysis as underserved (U), had a significant delay in obtaining germline genetic testing compared to the remainder of patients (not underserved, NU) (U: 92d, NU: 21d, u=305.5, p=0.0016). In addition, African American (AA) patients had a significant delay of testing compared to White (W) patients (AA: 92d, W: 13d, u=161.5, p=0.0002). Furthermore, all 11 patients (1 Asian, 10 White) who obtained pre-diagnostic testing were NU patients (χ 2 =5.005, p=0.025). Upon further analysis, patients who have social work (SW) needs have a significant delay in testing compared to patients without SW needs (SW: 109d, no SW: 23d, u=263, p=0.025). Of the 12 patients who have SW needs, the primary needs were home care, transportation, or financial assistance. In addition, there was a trend toward difference between English (E) and non-English (NE) speaking patients when comparing their delays in testing (E=26.5, NE=108.5, u=257, p=0.12). Conclusions: Analysis of germline and clinical data from our 305-patient cohort identified a striking and concerning negative correlation between patient income and delays in germline testing. In addition, underserved patients had significant delays in germline testing and did not obtain any pre-diagnostic testing. Furthermore, social needs and primary language may be barriers for germline testing. Interprofessional collaborations may be required to prompt germline testing at our institution or nationwide.
LAG3-related factors to predict response to nivolumab monotherapy in advanced gastric cancer (WJOG10417GTR study).
Authors: Kai Tsugaru, Narikazu Boku, Chie Kudo-Saito, Hirokazu Shoji, Hiroshi Imazeki, Naoki Takahashi, Takeshi Kawakami, Yusuke Amanuma, Takeru Wakatsuki, Naohiro Okano, Yukiya Narita, Yoshiyuki Yamamoto, Rika Kizawa, Kengo Nagashima, Kazunori Aoki, Kei Muro
Journal: Journal of Clinical Oncology (2023)

425 Background: Blocking immune checkpoint (IC) pathways, particularly mediated by PD1 and PDL1, has attracted great attention as a promising strategy for treating gastrointestinal cancer. However, the clinical responses are low in many cases, and thus a new treatment strategy and its biomarker are urgently needed for improving the clinical outcome. Blocking other IC molecules, including LAG3, has been evaluated in many clinical trials, while the therapeutic efficacy and the predictive biomarkers remains to be determined due to the same issues as anti-PD1/PDL1 therapy. Methods: We analyzed soluble LAG3 (sLAG3) in sera by ELISA, and LAG3 + cells by flow cytometry, using fresh peripheral blood (PB) obtained from 91 patients with advanced gastric cancer (AGC) before and about one month after nivolumab monotherapy (2 courses) in the WJOG10417GTR study, according to the protocol approved by the IRB (August 2018 - November 2020). Progression-free survival (PFS) and overall survival (OS) were compared between high/low groups divided by the cutoff value determined by visually assessing the continuous trend and change point of log hazard ratios obtained by applying penalized splines to each molecular marker. This study was supported by ONO PHARMACEUTICAL CO., LTD. and Bristol Myers Squibb. Results: Posttreatment values were significantly more associated with patients’ prognosis rather than baseline values, and the sLAG3-high group showed significantly shorter PFS/OS as compared to the low group divided by the median: median PFS (mPFS) 51.5 vs 95.5 days (HR = 2.04, P = 0.002), and median OS (mOS) 188 vs 393 days (HR = 1.81, P = 0.032). Patients with high levels of LAG3 + PBCs after treatment showed worse prognosis as compared to those with low levels divided by the cutoff values: a CD3 + CD4 + LAG3 + T-cell subset, mPFS 43 vs 72 days (HR = 2.23, P = 0.015) and mOS 178 vs 282 days (HR = 1.56, P = 0.249); a CD3 + CD8 + LAG3 + T-cell subset, mPFS 57 vs 69 days (HR = 1.89, P = 0.012) and mOS 228 vs 303 days (HR = 1.40, P = 0.233); and a CD56 + LAG3 + NK subset, mPFS 57 vs 88 days (HR = 2.15, P = 0.003) and mOS 217 vs 409 days (HR = 1.88, P = 0.031). Patients with sLAG3-high/CD56 + LAG3 + NK-high levels showed markedly worse prognosis than those with low/low levels (mPFS-HR = 10.55, P &lt; 0.001; and mOS-HR = 4.59, P &lt; 0.001). Conclusions: Patients with posttreatment high levels of sLAG3 and LAG3 + cells in PB showed poor prognosis of AGC patients after the nivolumab therapy, suggesting that these are useful predictive biomarkers. LAG3 may be a promising target in immunotherapy for AGC. Clinical trial information: UMIN000032686 .
Clinical implications of peritoneal cytology evaluated by staging laparoscopy for potentially resectable pancreatic cancer.
Authors: Haruyoshi Tanaka, Mina Fukasawa, Takamichi Igarashi, Toru Watanabe, Shiori Saeki, Ayaka Itoh, Kazuto Shibuya, Nana Kimura, Katsuhisa Hirano, Masakazu Nagamori, Kosuke Mori, Naoya Takeda, Takeshi Miwa, Isaya Hashimoto, Shozo Hojo, Koshi Matsui, Isaku Yoshioka, Tomoyuki Okumura, Tsutomu Fujii
Journal: Journal of Clinical Oncology (2023)

674 Background: Positive peritoneal cytology has been reported to indicate a poor prognosis in patients with pancreatic cancer even if the primary tumor is surgically resected. This study investigated the clinical implications of peritoneal cytology by staging laparoscopy for patients with potentially resectable pancreatic cancer for whom initial treatment will be started. Methods: We retrospectively reviewed 113 consecutive patients with pancreatic cancer diagnosed as resectable by computed tomography in whom peritoneal cytology was evaluated by staging laparoscopy between December 2018 and August 2022. Patients with positive cytology received induction chemotherapy, and those in whom cytology converted to negative underwent surgical resection as needed when possible. We set best tumor marker cutoff values for predicting positive cytology by maximizing the Youden index. Results: Seventy-three patients were men and the mean age was 72 years. Thirty patients (26.5%) had positive cytology at initial staging laparoscopy. Minimal peritoneal metastases were detected in seven of these patients and liver metastases in two. Larger tumor diameter ( &gt; 30 mm), location in the pancreatic body or tail, an elevated CA19-9 level ( &gt; 138.5 U/ml), an elevated CA125 level ( &gt; 13.5 U/ml), and an elevated CEA level ( &gt; 5.1 ng/ml) were associated with a significantly increased risk of positive cytology (odds ratio 4.71 [confidence interval 1.87–12.2] P = 0.001, 2.49 [1.07–6.05] P = 0.038, 2.95 [1.26–7.12] P = 0.014, 3.89 [1.57-10.7] P = 0.005, and 3.52 [1.23–10.2] P = 0.018, respectively). Eighteen patients (60%) who received induction chemotherapy converted from positive to negative cytology; seven (38%) of these patients underwent surgery and all remain alive without recurrence. Interestingly, median overall survival in patients with negative cytology was not necessarily inferior to that in those with positive cytology (23.4 months vs. 24.2 months, P = 0.33). Conclusions: Over a quarter of patients with pancreatic cancer that is diagnosed as resectable by computed tomography may have positive peritoneal cytology at the initial assessment. These patients tend to have higher CA19-9, CA125, and CEA levels, larger tumors, and tumors located in the body or tail of the pancreas. A more favorable prognosis may be achieved by administering induction chemotherapy until cytology converts to negative than by upfront surgery.
Unique microbial profile identified in patients with gastric cancer with pathologic response to neoadjuvant chemotherapy.
Authors: Harrison M. Drebin, Miseker Abate, Teng Fei, Laura H. Tang, Monika Laszkowska, Steven Brad Maron, Shoji Shimada, Santosha Vardhana, Chad Vanderbilt, Vivian E. Strong
Journal: Journal of Clinical Oncology (2023)

458 Background: Microbial dysbiosis has been shown to be associated with the pathogenesis of gastric cancer (GC). However, the relationship between the GC microbiome and response to systemic therapy, such as neoadjuvant chemotherapy (NAC), is largely unknown. This study aims to explore changes in the microbiome after neoadjuvant chemotherapy, by analyzing the microbial profile of patients who received NAC and comparing differences among those with varied pathologic response to therapy. Methods: A microbiome bioinformatics pipeline using multiple next generation sequencing platforms was developed and used for analysis. GC tissue from patients who received NAC (n=101) and those who did not (n=85) were acquired at the time of surgical resection. Shannon alpha diversity plot and enrichment analyses by odds ratio were used to compare the microbial differences of the treatment cohorts. The microbial profiles of patients with pathologic response to NAC (&gt;20% response) were characterized. Results: Of patients who received NAC, 66 (65.3%) experienced a greater than 20% response to NAC, and 35 (34.6%) demonstrated a 20% or lower response. Patients with a pathologic response to NAC were enriched for Rhizobium, Streptomyces, Comamonas, Sphingomonas, Micrococcus, Mycobacterium, Thauera, Hyphomicrobium, and Sinorhizobium (OR&gt;4). There were no statistically significant differences in alpha diversity (p&gt;0.05). Conclusions: Our results demonstrate that patients with a greater than 20% pathologic response to NAC have a distinct microbial enrichment compared to those with a poor pathologic response. Given the variable NAC treatment responses in GC, understanding unique microbial signatures in tumors will provide the landscape to explore key microbial contributors to GC NAC treatment response that may improve our understanding of treatment response variability among patients. [Table: see text]
Outcome of receiving lenvatinib following immunotherapy in patients with advanced hepatocellular carcinoma.
Authors: Jennifer Gile, Mathias Earl Palmer, Michael H. Storandt, Tanios S. Bekaii-Saab, Nguyen H. Tran, Amit Mahipal
Journal: Journal of Clinical Oncology (2023)

507 Background: Lenvatinib, a multikinase inhibitor, is an FDA approved treatment for advanced hepatocellular carcinoma (HCC) in the first line setting. Atezolizumab and bevacizumab are considered new standard of care as first line therapy after results of the IMBrave 150 trial. Currently, we do not have data to suggest any second-line treatment after administration of immunotherapy. We describe the clinical outcomes in patients with advanced HCC who received lenvatinib following treatment with immunotherapy. Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010 and 2021 at Mayo Clinic in Minnesota, Arizona, and Florida. The study was reviewed and approved by the intuitional review board. The primary outcomes were overall survival (OS) and progression free survival (PFS). Results: We identified 53 patients with advanced HCC who received lenvatinib following immunotherapy. Most patients (83%) were male. Median age at start of lenvatinib was 67 years old. Forty-two (79%) patients had a Child-Pugh score of A at diagnosis while 30 (58%) patients were still Child-Pugh A at time of lenvatinib initiation. Risk factors for HCC included Hep C (43%), alcohol use (34%), NASH (15%) and hepatitis B (7%). Forty-five (85%) patients received lenvatinib in the 2 nd line and 8 (15%) patients received it as third line or later. At time of data extraction, 38 (72%) patients had died. Median PFS was 4 months (95% CI: 3 – 6) and median OS from time of lenvatinib initiation was 13 months (95% CI: 6 – 24). The most common adverse events of any grade included fatigue (53%), hypertension (37%), AST elevation (30%), anorexia (28%), bilirubin elevation (25%) and diarrhea (25%). Twenty-one (40%) patients experienced grade 3 or higher adverse events including hypertension (25%), confusion (6%), acute kidney injury (2%), hyperkalemia (2%), ALT elevation (2%), proteinuria (2%), arthralgia (2%), heart failure (2%), AST elevation (2%), bilirubin elevation (2%), palmar-plantar erythrodysesthesia (2%), oral mucositis (2%), weight loss (2%), hypothyroidism (2%), anorexia (2%), fatigue (2%) and diarrhea (2%). Seven patients stopped treatment due to adverse events: 1 for hypertension, 2 for confusion, 1 for heart failure, 2 for fatigue, and 1 for elevated bilirubin. Conclusions: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown. We found that median OS was 13 months in patients who received lenvatinib after immunotherapy which is comparable to survival in other studies when used as first line therapy. Our experience demonstrates that patients may benefit from treatment with lenvatinib following initial progression on immunotherapy.
Development of a novel chimeric oncolytic viral platform, CF33 and its derivatives, for peritoneal-directed CF33-OV treatment of gastric cancer peritoneal carcinomatosis.
Authors: Annie Yang, Zhifang Zhang, Shyambabu Chaurasiya, Anthony K Park, Audrey Jung, Jianming Lu, Sang-In Kim, Saul Priceman, Yuman Fong, Yanghee Woo
Journal: Journal of Clinical Oncology (2023)

428 Background: Peritoneal carcinomatosis (PC) is a deadly end-stage manifestation of gastric cancer (GC). CF33, a chimeric oncolytic virus, and its genetically modified derivatives have shown exclusive cancer selectivity and oncolytic potency against various solid tumors. Intravenous and intratumoral CF33-hNIS and CF33-hNIS-antiPDL1 have entered phase I trials to treat triple-negative breast cancer and unresectable solid tumors. Here, we investigated the antitumor activities of CF33-OVs against GCPC. Methods: We infected six GC cell lines, including both intestinal-type (AGS and MKN-74) and diffuse-type (KATO III, MKN-45, SNU-1, and SNU-16) with CF33, CF33-GFP, or CF33-hNIS-antiPDL1 at various multiplicities (MOI 0.01, 0.1, 1.0 and 10.0) to examine viral proliferation and cytotoxicity by using standard plaque assay and cell proliferation assay. We performed immunofluorescence imaging and flow cytometric analysis to verify virus-encoded gene expression and blockade of PD-L1 binding by virus-encoded anti-PD-L1 scFv. A mouse model of peritoneal dissemination xenograft of SNU-16-ffluc cells was set up to evaluate the antitumor activity of intraperitoneal (IP) CF33-hNIS-antiPDL1 treatment (3x10 5 pfu x 3 doses). Results: CF33-OVs showed dose-dependent infection, replication, and killing of human GC cell lines. Immunofluorescence imaging showed virus-encoded GFP, hNIS, and anti-PD-L1 scFv expression in CF33-OV-infected GC cells. GC cell surface PD-L1 binding was blocked by virus-encoded anti-PD-L1 scFv. In the xenograft model, IP CF33-hNIS-antiPDL1 treatment significantly reduced peritoneal tumors (p&lt;0.0001), decreased amount of ascites (62.5% PBS vs. 25% CF33-hNIS-antiPLD1), and prolonged animal survival (p&lt;0.01). Conclusions: CF33-OVs demonstrate effective antitumor activity and can deliver functional proteins in vitro and in vivo. CF33-hNIS-antiPDL1 treatment induced sustained regression of GCPC and prolonged survival. These promising preclinical results support peritoneal-directed strategies with CF33-hNIS-antiPDL1 in GCPC patients.
Racial and ethnic disparities in multinational phase III clinical trials in liver and biliary tract cancer.
Authors: M. Cecilia Monge B., Katherine McGlynn, Tim F. Greten
Journal: Journal of Clinical Oncology (2023)

497 Background: Racial and ethnic diversity ensures validity of clinical research and opens novel oncologic treatments to all population groups. Hispanics and non-Hispanic Blacks (NHB) are the largest racial/ethnic groups in the United States after non-Hispanic Whites (NHW). Hispanics accounted for 19%, while NHB accounted for 14% of the population in 2021. From 2012 to 2019 the proportion of hepatocellular carcinomas (HCC) and biliary tract cancers (BTC) occurring in Hispanics was 23.2% and 22.6% respectively; the proportion of HCC and BTC occurring in NHB was 11.1% and 8.3% respectively. We examined the participation of NHB and Hispanics in multinational phase III clinical trials of HCC and BTC in the last ten years. A participant to population ratio (PPR) of 0.8-1.2 reflects adequate ethnic/racial representation; a lower PPR indicates underrepresentation. Methods: A database search was performed in PubMed, Embase and Web of Science: Core Collection (Cl for multinational phase III clinical trials of HCC or BTC, studying first and second line treatments published from August 2012 to August 2022.Trials meeting these criteria were identified and the percentage of NHB and Hispanics included was calculated and compared to the proportion of NHB and Hispanics affected by HCC and BTC as per the National Cancer Institute Surveillance, Epidemiology, and End Results Program. Results: Eighteen multinational phase III clinical trials studying first- and second-line treatments for HCC and BTC were identified. The trials enrolled a total of 12464 patients; 27% (n=5 trials) did not report racial/ethnic characteristics. Of the 9991 patients included in trials for which race/ ethnicity was provided, 11 (0.08%) were Hispanics and 88 (0.7%) were NHB. The participant to population ratio (PPR) in Hispanics for HCC was 0.003 and 0 for BTC, meanwhile the PPR in NHB was 0.6 for HCC and 0 for BTC. Conclusions: NHB and Hispanics are underrepresented in HCC and BTC in multinational phase III trials relative to the U.S population. Most patients included in trials were Asian, consistent with the global incidence of HCC. It may be important for phase III clinical trials seeking FDA approval to require mandatory racial/ethnic diversity that is reflective of the US population.